Interventions to Prevent Age- Related Cognitive Decline, Mild Cognitive Impairment, and Clinical Alzheimer s-type Dementia

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1 Interventions to Prevent Age- Related Cognitive Decline, Mild Cognitive Impairment, and Clinical Alzheimer s-type Dementia Minnesota Evidence-based Practice Center for the Health and Medicine Division, National Academy of Sciences, Engineering, and Medicine meeting October 25, 2016

2 Disclosures This presentation is based on a draft report of research conducted by the Minnesota Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No I). The findings and conclusions in this document are those of the authors who are responsible for its contents; the findings and conclusions do not necessarily represent the views of AHRQ. Therefore, no statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and Human Services. The draft report is subject to change after peer review. None of the investigators has any affiliations or financial involvement that conflict with the material presented in this report. 2

3 Objective To assess evidence for a variety of interventions aimed at preventing or delaying the onset of age-related cognitive decline, mild cognitive impairment (MCI), or clinical Alzheimer s-type dementia (CATD). 3

4 Data Sources Ovid Medline, Ovid PsycINFO, Ovid Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) to identify randomized controlled trials, nonrandomized controlled trials, and prospective cohort studies published and indexed in bibliographic databases between January 2009 and March Experts and prior reviews. Grey literature. 4

5 Review Methods Study Selection Reviewed titles and abstracts to identify appropriate studies. Data Extraction and Quality Assessment Extracted details on study design, participant characteristics, outcomes and adverse events. Assessed risk of bias using standard criteria and summarized those studies not judged to have high risk of bias. Data Synthesis and Analysis Summarized results in summary tables and synthesized evidence for each unique population, intervention, comparison, and outcome and harm. Because a highly varied set of tests was used across the studies, we grouped them into domains to facilitate analysis. Used a standard method to rate the strength of evidence for those studies that had sufficient sample size. 5

6 Results Bibliographic database searches 8,433 references Total for title and abstract review 8,516 references Pulled for full text review 1,158 references Eligible references=205 Hand search 83 references Title and abstract review excluded 7,358 references Excluded 953 references Excluded population = 311 Nonexperimental study design = 170 Inadequate followup time = 180 Not available in English = 18 Not intervention study = 181 No outcomes of interest = 48 Inadequate sample size = 45 6

7 Guide to Graphics Birds-eye view of patterns of statistically nonsignificant and significant findings Not forest plots distance from center line does not convey information Different symbols used to represent different outcomes One symbol per reported test result (may be multiple tests per domain and/or per study) Figures are not strength of evidence assessments Symbol Sizes Used Sample Sizes Represented N<100 N= N=501-1,000 N=1,001-5,000 N=5,001-10,000 N=10,001-15,000 N=15,000+ 7

8 Summary: Dementia or MCI incidence by intervention type Cognitive Training k=2, n=2,856 Physical Activity k=2, n=1,805 Nutraceuticals k=4, n=18,061 Hormone Therapy k=2, n=12,865 Vitamins k=3, n=25,195 SIGNIFICANT FAVORS I* =Dementia =Dementia or MCI NON-SIGNIFICANT* =Dementia =Dementia or MCI Antihypertensives k=4 n=23,150 Lipid Lowering Treatment k=1, n=20,536 NSAIDs k=1 n=2,528 Antidementia Medication k=1, n=769 Diabetes Medication k=1, n=12,537 Other Interventions k=1, n=45 SIGNIFICANT FAVORS C* =Dementia =Dementia or MCI *Categorized by whether results showed statistically significant differences between groups. I = intervention; C = control k = number of studies; n =sample size 8

9 Cognitive Training 11 eligible trials with low/medium ROB evaluated effects of cognitive training. The ACTIVE trial provided the strongest and most comprehensive design to assess the effect of cognitive training on cognitive performance for older adults with normal cognition. Intervention 6 weeks with boosters (non-random); 3 training arms targeted memory, reasoning, and processing speed, respectively; follow-up 10 years Results provide moderate-strength evidence at 2 years (but low-strength at 5 and 10 years due in part to attrition) that cognitive training can improve cognitive function in the domain trained, but effect on other domains was rare. 9

10 Cognitive Performance (ACTIVE Trial) 2-year Outcomes Ball 2002, n=2,832 Memory Training Reasoning Training Speed of Processing Training 5-year Outcomes Willis 2006, n=2,832 Memory Training Reasoning Training Speed of Processing Training 10-year Outcomes Rebok 2014, n=2,832 Memory Training Reasoning Training Speed of Processing Training Dementia Diagnosis (5-year) Unverzagt 2012, n=2,832 SIGNIFICANT* ŸResult favors I NON- SIGNIFICANT* Results were not statistically significant *Categorized by whether results showed statistically significant differences between groups. The nonsignificant results were for domains not trained, showing generally a lack of diffusion across domains. I = intervention; n =sample size 10

11 Cognitive Training 10 other (other than ACTIVE) eligible trials with low/medium ROB evaluated effects of cognitive training Interventions mostly ranged 5-16 wks, heterogeneous regarding cognitive domains trained, follow-up typically 6-12 months. Participants mostly performed better in cognitive tests in the domain matching their training, but not in other cognitive domains. 1 study that reported incident CATD and 3 that reported patient-reported memory, all in adults with MCI, showed mixed results 11

12 Cognitive Performance (other than ACTIVE) normal cognition Executive, Attention, Processing Speed Wollinsky 2013, n=681 Klusmann 2010, n=259 Stine-Morrow 2014, n=461 SIGNIFICANT* =Result favors I NON-SIGNIFICANT* =Results were not statistically significant Memory Miller 2013, n=84 Klusmann 2010, n=259 Carretti 2013, n=40 Stine-Morrow 2014, n=461 *Categorized by whether results showed statistically significant differences between groups. I = intervention; n =sample size 12

13 Cognitive Performance (other than ACTIVE) MCI SIGNIFICANT* =Result favors I Diagnosis Buschert 2012 & Forster 2011, n=24 Biomarkers Buschert 2012 & Forster 2011, n=24 Brief Cognitive Test Performance Buschert 2012 & Forster 2011, n=24 Multidomain Neuropsychological Performance Buschert 2012 & Forster 2011, n=24 Vidovich 2013, n=150 Executive, Attention, Processing Speed Buschert 2012 & Forster 2011, n=24 Herrera 2012, n=22 Kwok 2013, n=223 Vidovich 2013, n=150 Memory Buschert 2012 & Forster 2011, n=24 Rapp 2002, n=19 Herrera 2012, n=22 Vidovich 2013, n=150 NON-SIGNIFICANT* =Results were not statistically significant *Categorized by whether results showed statistically significant differences between groups. I = intervention; n =sample size 13

14 Physical Activity Interventions 14 eligible unique studies with low/moderate risk of bias of physical activity interventions examined a wide variety of activities potentially targeting different pathways to affect cognition. Low-strength evidence shows benefits in some cognitive domains with aerobic training interventions when compared to attention control in adults with normal cognition. Low-strength evidence shows that multicomponent physical activity and resistance training do not offer clear benefit in cognitive outcomes over attention control in adults with normal cognition. While the majority of the results showed little to no effect for resistance training, there were several instances of improvement in cognitive outcomes for resistance training compared with attention control. Evidence is insufficient to conclude whether physical activity prevents MCI or CATD incidence 14

15 Cognitive Performance: Physical Activity, normal cognition SIGNIFICANT* =Result favors I RESISTANCE TRAINING Executive, Attention, Processing Speed van de Rest 2014, n=55 Cassilhas 2007, n=43 Cassilhas 2007, n=42 Memory van de Rest 2014, n=55 Cassilhas 2007, n=43 Cassilhas 2007, n=42 AEROBIC TRAINING Diagnosis Lautenschlager 2008, =170 Brief Cognitive Test Performance Muscari 2010, n=120 Multidomain Neuropsychological Performance Lautenschlager 2008, =170 Executive, Attention, Processing Speed Antunes 2015, n=46 Lautenschlager 200, =170 Memory Antunes 2015, n=46 Lautenschlager 2008, =170 Adverse Events Lautenschlager 200, =170 NON-SIGNIFICANT* =Results were not statistically significant 15

16 Cognitive Performance: Physical Activity, normal cognition MULTICOMPONENT PHYSICAL ACTIVITY Diagnosis Sink 2015, n=1635 Brief Cognitive Test Performance Napoli 2014, n=53 Williamson 2009, n=102 Multidomain Neuropsychological Performance Sink 2015, n=1635 Executive, Attention, Processing Speed Sink 2015, n=1635 Napoli 2014, n=53 Taylor-Piliae 2010, n=95 Williamson 2009, n=102 Memory Sink 2015, n=1635 Napoli 2014, n=53 Williamson 2009, n=102 TAI CHI Executive, Attention, Processing Speed SIGNIFICANT* =Result favors I NON-SIGNIFICANT* =Results were not statistically significant Taylor-Piliae, 2010, n=93 16

17 Nutraceutical Interventions Low-strength evidence suggests omega-3 fatty acids and ginkgo biloba did not improve CATD incidence or cognitive performance in adults with normal cognition. Evidence is insufficient to conclude whether resveratrol or plant sterol/stanol esters improved CATD incidence or cognitive performance in adults with normal cognition. Few studies examined the effects of nutraceuticals on adults with MCI. 14 eligible unique studies with low/moderate risk of bias used in analysis 17

18 Diet Interventions Evidence is insufficient to conclude whether protein supplementation or energy-deficit diets affect cognitive performance or incidence of MCI or CATD 2 eligible unique studies with low/moderate risk of bias used in analysis 18

19 Multimodal Interventions Evidence is insufficient to conclude whether most multimodal interventions offer benefit for cognitive performance or incidence of MCI or CATD. Few studies have examined interventions with similar components. Low-strength evidence shows that a multimodal intervention composed of diet, physical activity, and cognitive training provides benefits in executive function/attention/processing speed cognitive performance outcomes. 7 eligible unique studies with low/moderate risk of bias used in analysis 19

20 Hormone Therapy Interventions Low-strength evidence suggests that estrogen therapy may slightly increase the risk of CATD and MCI when the two diagnostic categories are examined together. Low-strength evidence suggests that estrogen plus progestin therapy may slightly increase the risk of probable dementia. Overall, low-strength evidence shows no differences (few statistically significant differences) in cognitive outcomes between hormone therapy and placebo groups. 14 eligible unique studies with low/moderate risk of bias used in analysis 20

21 Vitamin Interventions In adults with normal cognition, moderate-strength evidence shows no benefit in cognitive performance for vitamin E (400 mg) in women. Low-strength evidence shows benefit for vitamin B12 versus placebo for executive/attention/processing speed, brief cognitive test performance, and memory even after 2-4 years of use. Low-strength evidence shows no benefit in cognitive performance for multivitamins, vitamin B12 with omega-3, vitamin C (in women), vitamin D with calcium (in women), vitamin E (in women), or beta carotene (in women). Low-strength evidence shows no benefit in incident MCI or CATD for multivitamins or vitamin D with calcium 15 eligible unique studies with low/moderate risk of bias used in analysis 21

22 Antihypertensive Treatment Among 4 trials that reported incident CATD outcomes, a stepped multiple agent antihypertensive medication regimen reduced dementia risk versus placebo in 1 trial, but the other 3 found no reduced risk versus placebo. Generally, low-strength evidence shows that antihypertensive treatment regimens versus placebo appear to have no benefit on cognitive test performance in adults with normal cognition. Moderate-strength evidence shows that ACE and Thiazide versus placebo and ARBs versus placebo have no benefit on brief cognitive screening tests. Low-strength evidence shows that intensive versus standard antihypertensive control appears to have no benefit on cognitive test performance. Low-strength evidence shows no benefit on cognitive test performance between different active antihypertensive medication treatment regimens compared with each other. 16 eligible unique studies with low/moderate risk of bias used in analysis 22

23 Lipid Lowering Treatment Evidence was insufficient to assess the effect of 5 years of statin treatment on the risk of incident CATD or for preventing MCI. In most studies 6 months of statin treatment either did not improve cognitive performance or evidence was insufficient. Low-strength evidence shows no benefit on brief cognitive test performance, executive/attention/processing speed, or memory for statin plus fenofibrate versus statin plus placebo in adults with normal cognition. Low-strength evidence from 3 trials shows less improvement at 6 months in executive/attention/processing speed for statin versus placebo. 7 eligible unique studies with low/moderate risk of bias used in analysis 23

24 Nonsteroidal Anti-inflammatory Drugs (NSAIDs) No evidence was available for effect of low-dose aspirin on MCI or CATD incidence. Low-strength evidence shows no benefit for low-dose aspirin on brief cognitive screening tests, multidomain neuropsychological performance, or memory, even with 10 years of use. Low-strength evidence shows no benefit for NSAIDs, including both selective and nonselective cyclooxygenase-2 (COX-2) inhibitors, to reduce CATD incidence, and multidomain neuropsychological performance, or memory, with 8 years of use. 2 eligible unique studies with low/moderate risk of bias used in analysis 24

25 Antidementia Treatments Low-strength evidence shows acetylcholinesterase inhibitor (AChEI) antidementia drugs did not reduce the incidence of CATD in persons with MCI; evidence is insufficient for persons with normal cognition. Low-strength evidence shows AChEIs show no significant effect on cognitive test performance in adults with MCI. 2 eligible unique studies with low/moderate risk of bias used in analysis 25

26 Diabetes Medication Treatment No studies reported on the effect of diabetes treatment on the risk of incident clinical diagnoses of MCI or CATD. In middle-aged older adults with diabetes and presumed normal cognition, low-strength evidence shows intensive versus standard glycemic control had no significant effect on cognitive performance. 4 eligible unique studies with low/moderate risk of bias used in analysis 26

27 Other Interventions Other interventions that have been explored include lithium, a nicotine patch, individual piano instruction, multitask rhythmic exercise to music, sleep interventions, or social engagement. Evidence on the effect of these interventions on risk of MCI, CATD, or cognitive test performance is insufficient. We found no relevant studies for depression treatments, smoking cessation, or community-level interventions. 3 eligible unique studies with low/moderate risk of bias (5 unique interventions in 5 studies high ROB) 27

28 Agreement of Biomarkers and Measures of Cognitive Performance Among the eligible studies that reported the effect of interventions on cognitive outcomes, only a few used biomarkers (17 studies) ; most of those used some form of brain imaging. The overall rate of agreement (significant benefit, no effect, significant harm) between biomarkers and cognitive testing was 61%. 80% of that agreement resulted from both approaches showing no effect. In 8 of 33 instances (24%) when the biomarker showed a significant result, there was agreement with a cognitive test. 28

29 Discussion: CATD Cognitive decline can be a precursor of dementia. Impairment below a designated threshold helps to define CATD and/or MCI. But not all decline leads to CATD, and we do not know whether interventions that show effects on selected areas of cognitive performance can also stave off dementing conditions ACTIVE trial was designed to address specific areas of cognitive performance, but not the incidence of CATD. Efforts to adapt it to this goal were impeded by poor measures of CATD and high attrition 29

30 Methods Issues Applying strength of evidence (SOE) criteria to largely negative studies poses challenges. The goal of rating SOE is to assess the level of confidence in the findings. How comfortable can we be that the negative results would not be overturned with further research? Some of the core elements of SOE are not as helpful for studies that show no effect. All but a few of the results showed small changes in scores expressed as a proportion of the score range. 30

31 Methods Issues Short follow-ups for studies of CATD Cognitive outcomes were assessed with a wide array of neuropsychologic tests Many studies tested participants at intervals not considered adequate for repeated applications of those tests We assessed three types of studies: 1) Trials purposefully developed to assess cognitive outcomes, 2) Add-on trials: trials of an intervention originally targeted at another outcome (e.g., hypertension) to which a cognitive outcome was appended, and 3) Prospective cohort studies: studies that categorized but do not assign an intervention Definition of intervention was vague and did not use analytic tools to simulate quasiexperimental design to address selection bias. 31

32 Suggestions for Future Research Priority should be given to interventions that already show some promise, most notably physical activity and cognitive training Although we cannot say with certainty that many interventions definitely have no effect, it seems unwise to prioritize work in areas that show little promise hormone replacement therapy, NSAIDs, statins, and antidiabetic treatment. The argument around antihypertensive treatment is different. Some studies showed benefit, but given the extant commitment to blood pressure reduction further studies of its role in preventing dementia should have lower priority. 32

33 The Research Dilemma Large number of studies with weak SOE that show primarily little or no effect A lot of tests done; hard to pool Basis for determining no effect differs from that for determining effect Should scarce resources be used to pursue these areas vis a vis areas with some promise? 33

34 Suggestions for Future Research Trials should be designed intentionally to study methods of slowing and preventing age-related cognitive decline and MCI and CATD incidence. Trials to observe clinically meaningful change in cognitive function must be long enough; trials that address dementia incidence must be even longer. For detection of impact on incident MCI and dementia, need longitudinal investigations with follow-up periods of 10 years or more 34

35 Factors Affecting Trial Design Specify cohort characteristics (e.g., subject age, presence or absence of known risk factors of cognitive decline, cognitively normal versus MCI, etc.) The older the incipient cohort, the shorter the necessary follow-up BUT effect may vary by subject age Whether outcomes are intended to detect a delay in cognitive decline or a reduction in dementia incidence Given that the causes of dementia are complex and multifactorial, studies should address interventions that modify multiple risk factors BUT then must sort through combined effects 35

36 Measurement Future research should employ a more consistent set of tests to assess cognitive performance. The baseline status of subjects needs to be better measured and documented Future research trials that include incident CATD as a study outcome require evaluation of subjects using formal diagnostic guidelines for dementia 36

37 Conclusion: Public Health Significance Many interventions are beneficial for other reasons, and most are without significant harms. How strong do findings need to be to recommend public health support? No intervention had strong evidence to delay or prevent cognitive decline, mild cognitive impairment, or dementia. Cognitive training improves cognitive performance target of training for adults with normal cognition, but little evidence supports diffusion of benefits to other cognitive areas or on dementia incidence. Benefit lasted for 2 years, but attrition impedes judgments about longer follow up periods. Some types of physical activity may benefit cognitive performance in some areas for adults with normal cognition, although the underlying mechanism is unclear. 37

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39 Study selection criteria - PICOTS PICOTS KQ 1 KQ 2 KQ3 Population Adults with normal cognition Adults with MCI Adults with normal cognition or MCI Intervention Interventions aimed at preventing, delaying, or slowing the development of age-related cognitive decline, incident MCI or CATD Interventions aimed at preventing, delaying, or slowing the development CATD The analysis will be limited to intermediate outcomes uncovered in KQs 1-2 Comparators Placebo Usual care Waitlist Information or attention control Active control Placebo Usual care Waitlist Information or attention control Active control NA Outcomes Final health or patient-centered outcomes: normal cognition, age-related cognitive decline, incident MCI or CATD Intermediate outcomes: Biomarker protein level(s) Cognitive test results Brain matter volume Brain cell activity level As determined by: Blood/CSF tests, Validated cognitive test results, and Brain scans Structural imaging - CT, MRI; PET Functional Imaging PET, fmri Molecular imaging PET, fmri, SPECT Final health or patient-centered outcomes: Incident CATD Intermediate outcomes: Biomarker protein level(s) Cognitive test results Brain matter volume Brain cell activity level As determined by: Blood/CSF tests, Validated cognitive test results, and Brain scans Structural imaging - CT, MRI;, PET Functional Imaging PET, fmri Molecular imaging PET, fmri, SPECT Adverse effects of intervention(s): Pharmacologic side effects, Psychological, Financial, Physical Final health or patient-centered outcomes: Incident MCI or CATD Adverse effects of intervention(s): Pharmacologic side effects, Psychological, Financial, Physical Timing Minimum followup of 6 months for intermediate Minimum followup of 6 months for intermediate None outcomes outcomes Settings Community-dwelling adults, including assisted living Community-dwelling adults, including assisted living Community-dwelling adults, including assisted living 39

40 Study selection criteria other criteria Category Study Enrollment Criteria for Inclusion For KQ1: Adults with normal cognition. For KQ2: Adults with MCI. For KQ3: Adults with normal or abnormal cognition who have had testing such as cognitive tests, blood/csf testing, or brain imaging used in intervention studies in KQ1 or KQ2. Study Objective For KQ1: To test the efficacy, comparative effectiveness, and harms of interventions to prevent, delay, or slow cognitive decline, onset of MCI, or clinical Alzheimer s-type dementia. For KQ2: To test the efficacy, comparative effectiveness, and harms of interventions to prevent, delay or slow clinical Alzheimer s-type dementia. For KQ3: To examine the association between biomarker and brain imaging outcomes and incidence of MCI of clinical Alzheimer s-type dementia. Study Design Outcomes Timing Publication Type Language of Publication For KQ1-2: RCTs and large prospective quasi-experimental cohort studies with comparator arms (n>250 per arm). For KQ3: Studies identified in KQs 1 and 2 Cognitive performance measured with validated instruments, biomarkers associated with clinical Alzheimer s-type dementia, and incident MCI or clinical Alzheimer s-type dementia For KQ1-2: Minimum followup of 6 months for intermediate outcomes. For KQ3: No minimum followup. Published in peer-reviewed journals and grey literature with full text available (if sufficient information to assess eligibility and risk of bias are provided). English 40

41 Risk of Bias of Individual Studies Overall confidence that the results were believable given the study limitations low, moderate or high Relevant components included: Participant selection Method of randomization or selection Blinding Allocation concealment Attrition Dual, independent assessment 41

42 Strength of Evidence Confidence that the findings will not change with further research insufficient, low, moderate, or high Graded when sufficient evidence (more than 1 study or 1 large study with n>500) Domains: Study limitations (overall risk of bias of the body of evidence) Directness (single, direct link between intervention and outcome) Consistency (similarity of effect direction and size) Precision (degree of certainty around an estimate) Reporting bias Strength of evidence assessed cautiously due to large number of comparisons with findings where intervention and comparison results not statistically significant. 42